Jérôme Tourret

Tenofovir Effect on the Kidneys of HIV-Infected Patients: A Double-Edged Sword?

Tenofovir disoproxil fumarate (TDF), the first nucleotidic inhibitor of HIV reverse transcription, became available in 2001. It has been extensively used worldwide and is now the most prescribed antiretroviral (ARV) drug. Its high antiviral activity and favorable metabolic profile are responsible for its success. Furthermore, TDF has been associated with other ARVs to form new combined antiretroviral treatments in only one tablet once-a-day, which increases treatment adherence. Fears of potential nephrotoxicity that tenofovir would have in common with two other drugs from the same family (adefovir, used to treat hepatitis B, and cidofovir, used to treat cytomegalovirus infections) were alleviated by the early clinical trials. Yet, in 2001, the first case of TDF-induced acute nephrotoxicity was published. Numerous cases have been published since then, and it is now established that TDF presents a tubular toxicity risk. Some facilitating factors have been identified, such as co-prescription of didanosine or boosted protease inhibitor, preexisting CKD, low body weight, and associated diabetes mellitus. Conversely, whether TDF is nephrotoxic in the long term is a highly debated question. Some studies suggest a decreased GFR when TDF is prescribed for a long period, while others indicate that TDF is safe for the kidneys even after many years of use. Here we review the differences in patient characteristics, study designs, and measured outcomes that can possibly explain these conflicting findings. We conclude with rational recommendation for appropriate TDF prescription.

High Recombinant Frequency in Extraintestinal Pathogenic Escherichia coli Strains

Homologous recombination promotes genetic diversity by facilitating the integration of foreign DNA and intrachromosomal gene shuffling. It has been hypothesized that if recombination is variable among strains, selection should favor higher recombination rates among pathogens, as they face additional selection pressures from host defenses. To test this hypothesis we have developed a plasmid-based method for estimating the rate of recombination independently of other factors such as DNA transfer, selective processes, and mutational interference. Our results with 160 human commensal and extraintestinal pathogenic Escherichia coli (ExPEC) isolates show that the recombinant frequencies are extremely diverse (ranging 9 orders of magnitude) and plastic (they are profoundly affected by growth in urine, a condition commonly encountered by ExPEC). We find that the frequency of recombination is biased by strain lifestyle, as ExPEC isolates display strikingly higher recombination rates than their commensal counterparts. Furthermore, the presence of virulence factors is positively associated with higher recombination frequencies. These results suggest selection for high homologous recombination capacity, which may result in a higher evolvability for pathogens compared with commensals.

The Conserved nhaAR Operon Is Drastically Divergent between B2 and Non-B2 Escherichia coli and Is Involved in Extra-Intestinal Virulence

The Escherichia coli species is divided in phylogenetic groups that differ in their virulence and commensal distribution. Strains belonging to the B2 group are involved in extra-intestinal pathologies but also appear to be more prevalent as commensals among human occidental populations. To investigate the genetic specificities of B2 sub-group, we used 128 sequenced genomes and identified genes of the core genome that showed marked difference between B2 and non-B2 genomes. We focused on the gene and its surrounding region with the strongest divergence between B2 and non-B2, the antiporter gene nhaA. This gene is part of the nhaAR operon, which is in the core genome but flanked by mobile regions, and is involved in growth at high pH and high sodium concentrations. Consistently, we found that a panel of non-B2 strains grew faster than B2 at high pH and high sodium concentrations. However, we could not identify differences in expression of the nhaAR operon using fluorescence reporter plasmids. Furthermore, the operon deletion had no differential impact between B2 and non-B2 strains, and did not result in a fitness modification in a murine model of gut colonization. Nevertheless, sequence analysis and experiments in a murine model of septicemia revealed that recombination in nhaA among B2 strains was observed in strains with low virulence. Finally, nhaA and nhaAR operon deletions drastically decreased virulence in one B2 strain. This effect of nhaAR deletion appeared to be stronger than deletion of all pathogenicity islands. Thus, a population genetic approach allowed us to identify an operon in the core genome without strong effect in commensalism but with an important role in extra-intestinal virulence, a landmark of the B2 strains.

Population Phylogenomics of Extraintestinal Pathogenic Escherichia coli

The emergence of genomics over the last 10 years has provided new insights into the evolution and virulence of extraintestinal Escherichia coli. By combining population genetics and phylogenetic approaches to analyze whole-genome sequences, it became possible to link genomic features to specific phenotypes, such as the ability to cause urinary tract infections. An E. coli chromosome can vary extensively in length, ranging from 4.3 to 6.2 Mb, encoding 4,084 to 6,453 proteins. This huge diversity is structured as a set of less than 2,000 genes (core genome) that are conserved between all the strains and a set of variable genes. Based on the core genome, the history of the species can be reliably reconstructed, revealing the recent emergence of phylogenetic groups A and B1 and the more ancient groups B2, F, and D. Urovirulence is most often observed in B2/F/D group strains and is a multigenic process involving numerous combinations of genes and specific alleles with epistatic interactions, all leading down multiple evolutionary paths. The genes involved mainly code for adhesins, toxins, iron capture systems, and protectins, as well as metabolic pathways and mutation-rate-control systems. However, the barrier between commensal and uropathogenic E. coli strains is difficult to draw as the factors that are responsible for virulence have probably also been selected to allow survival of E. coli as a commensal in the intestinal tract. Genomic studies have also demonstrated that infections are not the result of a unique and stable isolate, but rather often involve several isolates with variable levels of diversity that dynamically changes over time.

Néphrotoxicité des antirétroviraux autres que le ténofovir

The remarkable improvement of the outcome of HIV infection came with the price of substantial toxicity of some antiretrovirals. The first molecules used to treat HIV included an important nephrotoxicity. Zalcitabine, stavudine and didanosine can induce severe lactic acidosis. Lactate production is enhanced and the renal capacity to regulate pH is overwhelmed. However, this side effect is not due to a direct dysfunction of the kidneys. Zalcitabine was withdrawn from the market because of this risk. Indinavir, a protease inhibitor, is soluble only in very acidic solutions. Consequently, the small fraction that is excreted in the urine precipitates and can be responsible for uro-nephrolithiasis, leukocyturia, cristalluria, obstructive acute kidney failure, and acute or chronic interstitial nephritis. This is the reason why indinavir is almost not prescribed nowadays, even if it is still marketed. In addition to the direct nephrotoxicity of some antiretrovirals, anti-HIV treatment also includes a toxicity which pathophysiology is not completely elucidated. This nephrotoxicity is the consequence of organ accelerated ageing and of an increased vascular risk. Kidney vascularization (from renal arteries to capillaries) is essential to kidney function and all cardiovascular risks are also renal risks. It is now clearly established that combined antiretroviral treatment increases the vascular risk. A better comprehension of the links between HIV infection, its treatment and very long-term kidney risk is needed to improve the complex management of patients who have now cumulated several decades of HIV infection and treatment with various toxicities.

Severe Strongyloidiasis in Solid Organ Transplant Recipients: Should We Preventively Treat the Recipient, the Donor, or Both?

Strongyloidiasis is caused by a soil-transmitted helminth that is endemic in tropical and subtropical countries. The parasite can complete its life cycle without leaving the host, allowing autoinfection and persistence. The risk of infection in travelers is low, but the disease may become lethal following immunosuppression. In case of solid organ transplantation, the risk of donor transmission has been suspected for several years. However, the management of live donors in this context has only recently been considered, and no guidelines exist for the management of deceased donors. To highlight the complexity of diagnosing, treating, and preventing strongyloidiasis donor transmission, we describe a case of possible transmission of severe strongyloidiasis to a kidney transplant recipient with limited travel history. Taking into account the difficulty of diagnosing chronic strongyloidiasis infection and the increase in travel and immunosuppressive treatments, we recommend pragmatic management guidelines to limit the risks of infection.

Manque d’énergie chez un patient vivant avec le VIH

Un homme caucasien âgé de 58 ans fut admis dans notre service pour exploration d’une insuffisance rénale aiguë. Son principal antécédent était une infection par le VIH, découverte 25 ans auparavant, avec un traitement antirétroviral débuté il y a 15 ans. L’évolution de la maladie avait été marquée par une pneumopathie aiguë et une maladie de Castleman requérant un traitement par étoposide (deux mois avant l’épisode actuel). Son traitement antirétroviral était constitué d’une trithérapie par emtricitabine, ténofovir-disoproxil-fumarate (TDF), et darunavir potentialisé par du ritonavir. Ses autres traitements étaient l’acide folique, l’ésoméprazole, l’amitryptiline et l’aspirine. Environ deux semaines avant l’hospitalisation, le patient a présenté une asthénie associée à des vomissements intenses et des diarrhées entraı̂nant une perte de poids de 4 kg. Le patient a également remarqué une diminution de sa diurèse. À l’admission dans le service, le patient est apyrétique et sa fréquence cardiaque est normale. La pression artérielle est à 100/60 mmHg. L’examen physique est sans particularité. La biologie retrouve une insuffisance rénale aiguë avec une créatininémie à 685 mmol/L contre 54 mmol/L trois mois auparavant. La kaliémie est à 2,8 mmol/L, la réserve alcaline à 28 mmol/L, la natrémie à 122 mmol/L, la calcémie (corrigée par l’albuminémie) à 2 mmol/L, la phosphorémie à 1,15 mmol/L et la magnésémie à 1,22 mmol/L. Le bilan hépatique et la numération formule Fig. 1. Image principale : biopsie rénale du patient (coloration à l’hématoxyline et à l’éosine, grossissement 100). Encadré en bas à gauche : trichrome de Masson (grossissement 400). Disponible en ligne sur